Continuation of empirical antimicrobial therapy (EAT) for febrile neutropenia in patients with haematological malignancies until neutrophil recovery could prolong the therapy innecessarily.

We did an investigator-driven, superiority, open-label, randomised, controlled phase 4 clinical trial in six hospitals in Spain. For the experimental group, EAT was withdrawn after 72 h or more of apyrexia plus clinical recovery; for the control group, treatment was withdrawn when the neutrophil count was also 0•5 × 10⁹ cells per L or higher. The primary efficacy endpoint was the number of EAT-free days.

The mean number of EAT-free days was significantly higher in the experimental group than in the control group (16•1 [SD 6•3] vs 13•6 [7•2], absolute difference –2•4 [95% CI –4•6 to –0•3]; p=0•026).

Conclusion: In high-risk patients with haematological malignancies and febrile neutropenia, EAT can be discontinued after 72 h of apyrexia and clinical recovery irrespective of their neutrophil count. This clinical approach reduces unnecessary exposure to antimicrobials and it is safe.

This study builds on the existing evidence by clarifying the optimal duration of EAT in patients with haematological malignancies and febrile neutropenia without microbiological documentation. These findings provide evidence supporting the European Conference of Infections in Leukaemia (ECIL) recommendations.

This insight could contribute to changes in clinical practice, resulting in a reduction in antibiotic pressure in these patients without increasing the frequency of recurrent fever, secondary infections, or mortality.